Rainer H Müller

Freie Universität Berlin, Berlín, Berlin, Germany

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Publications (139)412.68 Total impact

  • Tao Liu · Rainer H Müller · Jan P Möschwitzer ·
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    ABSTRACT: Introduction: The top-down approach is frequently used for drug nanocrystal production. A large number of review papers have referred to the top-down approach in terms of process parameters such as stabilizer selection. However, a very important factor, that is, the influence of drug properties, has been not addressed so far. Areas covered: This review will first discuss different nanocrystal technologies in brief. The focus will be on reviewing the different drug properties such as solid state and particle morphology on the efficiency of particle size reduction during top-down processes. Furthermore, the drug properties in the final nanosuspensions are critical for drug dissolution velocity. Therefore, another focus is the characterization of drugs in obtained nanosuspension. Expert opinion: Drug physical properties play an important role in the production efficiency. The combinative technologies using modified drugs could significantly improve the performances of top-down processes. However, further understanding of the drug millability and homogenization will still be needed. In addition, a carefully established characterization system for nansuspension is essential.
    Expert Opinion on Drug Delivery 06/2015; 12(11):1-14. DOI:10.1517/17425247.2015.1057566 · 4.84 Impact Factor
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    ABSTRACT: The surface properties of intravenously injected nanoparticles determine the acquired blood protein adsorption pattern and subsequently the organ distribution and cellular recognition. A series of poly[acrylonitrile-co-(N-vinyl pyrrolidone)] (PANcoNVP) model nanoparticles (133-181nm) was synthesized, in which the surface properties were altered by changing the molar content of NVP (0-33.8mol%) as the more hydrophilic repeating unit. The extent of achieved surface property variation was comprehensively characterized. The residual sodium dodecyl sulfate (SDS) content from the synthesis was in the range 0.3-1.6μgml(-1), potentially contributing to the surface properties. Surface hydrophobicity was determined by Rose Bengal dye adsorption, hydrophobic interaction chromatography (HIC) and aqueous two-phase partitioning (TPP). Particle charge was quantified by zeta potential (ZP) measurements including ZP-pH profiles. The interaction with proteins was analyzed by ZP measurements in serum and by adsorption studies with single proteins. Compared to hydrophobic polystyrene model nanoparticles, all PANcoNVP particles were very hydrophilic. Differences in surface hydrophobicity could be detected, which did not linearly correlate with the systematically altered bulk composition of the PANcoNVP nanoparticles. This proves the high importance of a thorough surface characterization applying a full spectrum of methods, complementing predictions solely based on bulk polymer composition. Copyright © 2015. Published by Elsevier B.V.
    International Journal of Pharmaceutics 03/2015; 485(1-2). DOI:10.1016/j.ijpharm.2015.02.072 · 3.65 Impact Factor
  • Maria L. A. D. Lestari · Rainer H. Müller · Jan P. Möschwitzer ·
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    ABSTRACT: The role of a surface modifier is important in the formation of stable nanosuspensions. In this study, a simple and systematic screening method for selecting optimum surface modifiers was performed by utilizing a low-energy wet ball milling method. Nine surface modifiers from different classes with different stabilization mechanisms were applied on six different models of active pharmaceutical ingredients (API). Particle size analysis showed that at concentration five times higher than the critical micelle concentration, SDS and sodium cholate (anionic surfactant) showed the highest percent success to produce stable nanosuspensions with particle size smaller than 250 nm. Similar findings were also shown by poloxamer 188 (nonionic surfactant) and hydroxypropylmethylcellulose E5 (polymeric stabilizer) at concentration 1% (w/v) and 0.8% (w/v), respectively. In addition, combinations of anionic surfactant and nonionic surfactant as well as combinations of anionic surfactant and polymeric stabilizer showed high percent success in the formation of stable nanosuspensions. In general, no correlation can be found between the physicochemical characteristics of the model API (molecular weight, melting point, log P, pKa, and crystallinity) with its feasibility to be nanosized. The concentration and the principle of stabilization of surface modifier determine the formation of stable nanosuspensions. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
    Journal of Pharmaceutical Sciences 01/2015; 104(3). DOI:10.1002/jps.24266 · 2.59 Impact Factor
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    ABSTRACT: For the development of ultra-small NLC (usNLC) the determination of the required HLB (hydrophilic lipophilic balance) was found to be a suitable method, i.e., usNLC with a size below 50 nm were obtained by this method. Loading with 5% (w/w) coenzyme Q10 (Q10) led to usNLC with a size of about 85 nm. In comparison to classical NLC with a size of 230 nm and a nanoemulsion with similar size, the Q10 loaded usNLC show a higher release, a higher antioxidant capacity, and a better skin penetration for Q10. The reason for this is a flip–flop core–shell structure of the lipid matrix, i.e., the oil with dissolved active is surrounding the solid lipid based core. As the flip–flop structure was probably achieved by admixing high contents of liquid lipid, oil enriched usNLC might represent a novel and promising carrier system for the improved delivery of lipophilic actives.
    International Journal of Pharmaceutics 12/2014; 477(1). DOI:10.1016/j.ijpharm.2014.10.029 · 3.65 Impact Factor
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    ABSTRACT: UV irradiation leads to formation of reactive oxygen species (ROS). An imbalance between the antioxidant system and ROS can lead to cell damage, premature skin aging or skin cancer. To counteract these processes, antioxidants such as coenzyme Q10 (CoQ10) are contained in many cosmetics. To improve and optimize cell/ tissue penetration properties of the lipophilic CoQ10, ultra-small lipid nanoparticles (usNLC) were developed. The antioxidant effectiveness of CoQ10-loaded usNLC compared to conventional nanocarriers was investigated in the human keratinocyte cell line HaCaT. Using confocal laser scanning microscopy investigations of the carriers additionally loaded with nile red showed a clear uptake into cells and their distribution within the cytoplasm. By use of the XTT cell viability test, CoQ10 concentrations of 10 to 50μg/ ml were shown to be non-toxic, and the antioxidant potential of 10 μg/ml CoQ10 loaded usNLC in the HaCaT cells was analyzed via electron paramagnetic resonance spectroscopy after cellular exposure to UVA (1J/ cm(2)) and UVB (18mJ/ cm(2)) irradiation. In comparison to the CoQ10-loaded conventional carriers, usNLC-CoQ10 demonstrated the strongest reduction of the radical formation; reaching up to 23% compared to control cells without nanocarrier treatment. Therefore, usNLC-CoQ10 are very suitable to increase the antioxidant potential of skin. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmaceutics and Biopharmaceutics 12/2014; 89. DOI:10.1016/j.ejpb.2014.12.008 · 3.38 Impact Factor
  • Qionghua Wei · Cornelia M Keck · Rainer H Müller ·
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    ABSTRACT: The CapsMorph(®) technology prepares amorphous drugs for oral delivery by encapsulating them into porous materials. Hesperidin as model compound was loaded onto AEROPERL(®) 300 Pharma using the wetness impregnation method. Hesperidin was dissolved in dimethyl sulfoxide (DMSO) and alternatively in DMSO with addition of Tween 80. The drug solutions were added dropwise to the porous material and subsequently DMSO was evaporated. The AEROPERL(®) 300 Pharma could be loaded with about 30% hesperidin in the amorphous form. Amorphous state was verified by X-ray diffraction and differential scanning calorimetry. The CapsMorph(®) formulation was compared regarding properties determining oral bioavailability, i.e., kinetic saturation solubility and dissolution rate to raw drug powder and hesperidin nanocrystals. The saturation solubility of CapsMorph(®) without Tween 80 was 654μg/ml, which is 36-fold higher than the raw drug powder (18μg/ml) and about 20 times higher than nanocrystals (30μg/ml). In vitro release was faster (100% in 10min at pH 6.8) compared to dissolution of nanocrystals with about 15%. Addition of Tween 80 to CapsMorph(®) lowered the solubility (168μg/ml) and slowed down the release, but provided longer times of supersaturation without precipitation of drug. Based on these data, it appears that drug loaded porous materials provide better formulation compared to nanocrystals for poorly soluble drugs. Copyright © 2014. Published by Elsevier B.V.
    International Journal of Pharmaceutics 11/2014; 482(1-2). DOI:10.1016/j.ijpharm.2014.10.068 · 3.65 Impact Factor
  • Gregori B Romero · Run Chen · Cornelia M Keck · Rainer H Müller ·
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    ABSTRACT: Industrial concentrates of hesperidin nanocrystals (5.0% nominal concentration) were produced applying the smartCrystal(®) combination technology of wet bead milling and subsequent high pressure homogenization. Stabilization was performed by Kolliphor(®) P 188, preservation by Euxyl PE 9010 and glycerol. Physical and chemical stability were monitored over 1.5 years of storage at 4-6°C. The size of the bulk population stayed unchanged with about 250nm (photon correlation spectroscopy). Absence of crystal growth by Ostwald ripening and absence of agglomerates were shown by laser diffraction (LD) and light microscopy. The LD diameter 90% was still 0.7μm after 1.5 years. Despite the large surface of the nanosuspension in contact with the water phase, the chemical content proved also stable, only a reduction by 0.15% from 5.70% to 5.55% content was observed. The nanocrystals kept their crystalline state unchanged as shown by X-ray diffraction. The saturation solubility of the nanosuspension was more than triple compared to the raw drug powder in water. The data show the availability of a stable hesperidin concentrate as intermediate for industry to produce dermal formulations. Copyright © 2014. Published by Elsevier B.V.
    International Journal of Pharmaceutics 11/2014; 482(1-2). DOI:10.1016/j.ijpharm.2014.11.039 · 3.65 Impact Factor
  • Sven Staufenbiel · Cornelia M. Keck · Rainer H. Müller ·
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    ABSTRACT: The surface hydrophobicity of nanoparticles is one factor determining blood protein adsorption after intravenous administration, thus the organ distribution. Hydrophobic surfaces lead to opsonization and uptake by the liver macrophages, when hydrophilic nanoparticles avoid this and can circulate in the blood. To predict, at least to a certain degree, the in vivo distribution, the surface hydrophobicity needs to be measured and quantified. Methods need to be used which quantify hydrophobicity of nanoparticles in liquid environment similar to the body situation (= real environment), not using e.g. dry methods from tabletting. Different of those methods are mentioned in this work. In the present study the hydrophobicity of differently coated azithromycin nanocrystals was analyzed with hydrophobic interaction chromatography (HIC) and aqueous two-phase partitioning (TPP). Investigated stabilizers were Poloxamer 188, Poloxamer 407, caprylyl/capryl polyglucoside (Plantacare® 810), decyl polyglucoside (Plantacare® 2000), polyethylene glycol (PEG)-20 sorbitan monooleate (Tween 80) and tocopheryl polyethylene glycol succinate. HIC results revealed that coating with PEG free Plantacares leads to more hydrophobic surfaces (e.g. Plantacare 2000 retention time (tr) = 17.0 ± 1.9 min and tr = 6.5 ± 0.1 min for Tween 80), when also an increase of the amount of polypropylene glycol (PPG) in the Poloxamers lead to a stronger retention. Furthermore, PEG containing samples were analyzed by TPP whereby HIC results could be confirmed. Additionally, TPP showed differences between stabilizers having only 1 PEG chain and stabilizers with more than 1 PEG chain. In perspective, these stabilizers leading to a low hydrophobicity are promising candidates for further in vivo studies due to a decreased opsonization.
    Macromolecular Symposia 11/2014; 345(1). DOI:10.1002/masy.201400061
  • Sven Staufenbiel · Christoph Weise · Rainer H. Müller ·
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    ABSTRACT: The organ distribution of intravenously injected nanoparticles is determined by the composition of the blood protein adsorption pattern occurring after injection. This is exploited in the concept of “differential protein adsorption” for drug targeting, which is briefly discussed. The surface properties of the nanoparticles determine the adsorption patterns, by controlling the surface properties one can generate adsorption patterns required for achieving the desired organ distribution. The efficiency of this principle is shown by reviewing different organ distributions achieved using various polymeric nanoparticles with different surface properties. Surface modification can be obtained by polymer adsorption and can create nanoparticles circulating in the blood, or accumulating in targets such as bone marrow and brain. The protein adsorption patterns were analyzed using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Here, adsorption patterns of dendritic polymer nanoparticles were investigated, where the used polymer was dendritic polyglycerol sulfate. They showed reduced opsonization and preferential adsorption of apolipoprotein A-I with brain targeting potential. In perspective, the principle of surface property modification by polymer/stabilizer adsorption can be transferred to intravenous drug nanocrystals. A hybrid system of nanocrystal and polymeric nanoparticles is suggested, the polymeric nanoparticle with nanocrystal core.
    Macromolecular Symposia 11/2014; 345(1). DOI:10.1002/masy.201400062
  • Xuezhen Zhai · Jürgen Lademann · Cornelia M. Keck · Rainer H. Müller ·
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    ABSTRACT: Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1-10 μg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16 mg/ml at 20°C). Penetration should be increased by a) further increase in solubility and b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water-ethanol (1:9) and ethanol-propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol(®) 981 (non-neutralized) yielded stable nanosuspensions over 2 months at 4°C and room temperature. Storage at 40°C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol(®) 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept.
    European Journal of Pharmaceutics and Biopharmaceutics 09/2014; 88(1). DOI:10.1016/j.ejpb.2014.07.002 · 3.38 Impact Factor
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    ABSTRACT: Alkyl polyglycosides (APGs) represent a group of nonionic tensides with excellent skin compatibility. Thus they seem to be excellent stabilizers for lipid nanoparticles for dermal application. To investigate this, different APGs were selected to evaluate their influence on the formation and characteristics of solid lipid nanoparticles (SLN). Contact angle analysis of the aqueous solutions/dispersions of the APGs on cetyl palmitate films revealed good wettability for all APG surfactants. Cetyl palmitate based SLN were prepared by hot high pressure homogenization and subjected to particle size, charge and inner structure analysis. 1% of each APG was sufficient to obtain SLN with a mean size between 150nm and 175nm and a narrow size distribution. The zeta potential in water was ∼ -50mV; the values in the original medium were distinctly lower, but still sufficient high to provide good physical stability. Physical stability at different temperatures (5°C, 25° and 40°C) was confirmed by a constant particle size over an observation period of 90 days in all dispersions. In comparison to SLN stabilised with classical surfactants, e.g. Polysorbate, APG stabilised SLN possess a smaller size, improved physical stability and contain less surfactant. Therefore, the use of APGs for the stabilization of lipid nanoparticles is superior in comparison to classical stabilizers. Further, the results indicate that the length of the alkyl chain of the APG influences the diminution efficacy, the final particle size and the crystallinity of the particles. APGs with short alkyl chain led to a faster reduction in size during high pressure homogenization, to a smaller particle size of the SLN and to a lower recrystallization index, i.e. to a lower crystallinity of the SLN. The crystallinity of the SLN increased with an increase in the alkyl chain length of APGs. Therefore, by using the tested APGs differing in the alkyl chain length, not only small sized and physically stable but also SLN with different sizes and crystallinity can be obtained. An optimised selection of these stabilizers might therefore enable the production of lipid nanoparticles with "tailor-made" properties.
    International Journal of Pharmaceutics 08/2014; 474(1-2). DOI:10.1016/j.ijpharm.2014.08.008 · 3.65 Impact Factor
  • Xuezhen Zhai · Jürgen Lademann · Cornelia M Keck · Rainer H Müller ·
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    ABSTRACT: After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g., rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol(®) 981 (e.g., 20% caffeine in ethanol-propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process, e.g., 660nm (optimal for hair follicle accumulation) to 250nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept.
    International Journal of Pharmaceutics 05/2014; 470(1-2). DOI:10.1016/j.ijpharm.2014.04.060 · 3.65 Impact Factor
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    ABSTRACT: Polyhydroxy surfactants are nonionic ethylene oxide free stabilizers known for their complimentary dermatological properties and favorable environmental profile. The aim of this study was to develop solid lipid nanoparticles (SLN) stabilized with polyhydroxy surfactants varying in the chemical structure and to investigate the influence of the surfactants on the characteristics of the particles. Particles were produced by hot high pressure homogenization and the physico-chemical properties, e.g. contact angle, particle size, size distribution, zeta potential and crystallinity were determined. Results showed that the chemical structure of the surfactants influences the contact angle, particle size and crystallinity. Furthermore, the low surfactants concentration used (1% (w/w)) allowed the formation of the particles with a mean size below 200 nm, polydispersity index lower than 0.1 and sufficient physical stability for at least 6 months. As postulated by the zeta potential analysis stabilization ability of the surfactants was attributed to the superposition of electrostatic and steric effect which complement each other. All SLN formulations consisted of the same lipid matrix, but were found to possess different crystallinity indices. These differences are obviously created by the differences in the chemical structure of the surfactants. Therefore, the polyhydroxy surfactants investigated in this study can be judged to be novel suitable stabilizers for the formulation of well-skin tolerable SLN. The use of specific chemical structures of the surfactants can be used for the production of “tailor-made” SLN in the future.
    Colloids and Surfaces A Physicochemical and Engineering Aspects 03/2014; 444:15–25. DOI:10.1016/j.colsurfa.2013.12.023 · 2.75 Impact Factor
  • Patrik Scholz · Anja Arntjen · Rainer H Müller · Cornelia M Keck ·
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    ABSTRACT: The ARTcrystal(®) process is a new approach for the production of drug nanocrystals. It is a combination of a special pre-treatment step with subsequent high pressure homogenization (HPH) at low pressures. In the pre-treatment step the particles size is already reduced to the nanometer range by use of the newly developed ART MICCRA rotor-stator system. In this study, the running parameters for the ART MICCRA system are systematically studied, i.e. temperature, stirring speed, flow rate, foaming effects, size of starting material, valve position from 0° to 45°. The antioxidant rutin was used as model drug. Applying optimized parameters, the pre-milling yielded already a nanosuspension with a photon correlation spectroscopy (PCS) diameter of about 650nm. On lab scale production time was 5min for 1L nanosuspension (5% rutin content), i.e. the capacity of the set up is also suitable for medium industrial scale production. Compared to other nanocrystal production methods (bead milling, HPH etc.), similar sizes are achievable, but the process is more cost-effective, faster in time and easily scale-able, thus being an interesting novel process for nanocrystal production on lab and industrial scale.
    International Journal of Pharmaceutics 02/2014; 465(1-2). DOI:10.1016/j.ijpharm.2014.02.026 · 3.65 Impact Factor
  • Jaime Salazar · Rainer H. Müller · Jan P. Möschwitzer ·

    01/2014; 2014(9-10):1-14. DOI:10.1155/2014/265754
  • Abdulwahab Barakat · Ranjita Shegokar · Michael Dittgen · Rainer H. Müller ·
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    ABSTRACT: Coenzyme Q10 (Q10) has a poor bioavailability due to its very low aqueous solubility and high molecular weight. The purpose of this review is to discuss the different types of Q10 drug delivery systems (DDS) ranging from the simple oily dispersions to the nanotechnology-oriented systems such as nanocrystals, self-nanoemulsified drug delivery systems, etc. to overcome the solubility issue. The basics of these approaches were discussed in relationship to the effect of Q10 absorption. For that purpose, the percentage of the drug absorbed to the blood stream out of the administered dose was calculated as the fraction absorbed (Fa%). The Fa% for the nanoemulsions discussed in this article did not correlate with droplet size. In human studies most of the delivery systems had a low Fa% being in the range from 1.53 to 12.48 %. The highest Fa% value was found to be for the self-emulsified drug delivery systems (SEDDS). In dogs studies, the Fa% values ranged between 0.28 (cyclodextrin complex) and 4.8 %. In rat studies, some other DDS like emulsions and solubilized formulations showed Fa% of around 0.22 %. The relationship between the average Fa% in rats, dogs and humans was found to be 1:15:20. One recent study applied both oral and intravenous delivery of Q10; the orally tested SEDDS formulation had an absolute bioavailability of 2.2 % corresponding to Fa% = 0.04 %. The studies with Q10 formulations based only on in vitro data were also discussed and assessed regarding the influence of formulation on solubility, release and/or uptake.
    Journal of Pharmaceutical Investigation 12/2013; 43(6). DOI:10.1007/s40005-013-0101-4
  • Biswadip Sinha · Rainer H Müller · Jan P Möschwitzer ·
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    ABSTRACT: Cavi-precipitation process is a combinative particle size reduction technology based on solvent-anti-solvent precipitation coupled high pressure homogenization (HPH). The cavi-precipiation can be used for the efficient production of drug nanocrystals (NC) with improved dissolution rate leading to better bioavailability. The work presented here demonstrates the advantage of cavi-precipitation process over the standard HPH processes and standard combination process (decoupled process) where precipitation is performed outside the homogenizer. The model compound ibuprofen (IBP) was solubilized in isopropanol (IPA) to constitute the solvent phase and mixed with the anti-solvent phase (0.1% (w/v) hydroxypropyl methylcellulose with 0.2% (w/v) sodium dodecyl sulphate) at different ratios to carry out the precipitation step. IBP-IPA-Water composition was selected from ternary diagram for a highly supersaturated zone to obtain smaller size particles. The mean particle size [d(0.5)] obtained by this process (300nm) was much smaller when compared to that obtained from the decoupled process (1.5μm). Optimization of the solvent-anti-solvent ratio and drug concentration was necessary to achieve a smaller particle size. PXRD and DSC results revealed that the solid state properties of the original IBP and the prepared NC samples by cavi-precipitation samples were similar.
    International Journal of Pharmaceutics 10/2013; 458(2). DOI:10.1016/j.ijpharm.2013.10.025 · 3.65 Impact Factor
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    ABSTRACT: Abstract Objective: To prepare stable and easy to handle formulation of solid lipid nanoparticles (SLNs) by freeze-drying with or without cryoprotectants, as appropriate. Materials and methods: SLNs were freeze-dried without cryoprotectants or with cryoprotectants in quantities selected by freeze-thaw test (sucrose, glucose) or literature search (trehalose, maltose). Appearance, re-dispersability and size distribution of re-dispersed samples were evaluated. Results: SLN could be freeze-dried using 10% sucrose, trehalose or maltose. Trehalose was effective in protecting one of presented formulations that was already very stable on its own; its efficiency in protecting other two formulations was limited. Discussion: Our results are in line with various reports of successful freeze-drying of SLN, but considering the stability of original dispersions, no improvement was achieved. Conclusion: We confirmed that trehalose is among the most suitable cryoprotectant for SLN, however it did not improve shelf-life of the most stable formulation.
    Pharmaceutical Development and Technology 10/2013; 19(8). DOI:10.3109/10837450.2013.840846 · 1.20 Impact Factor
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    Rachmat Mauludin · Rainer H. Müller ·
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    ABSTRACT: Formulations of the rutin nanosuspensions have been prepared by high pressure homogenization (HPH). A Micron LAB 40 was used for HPH to obtain rutin nanosuspensions. Photon correlation spectroscopy (PCS) and laser diffraction were employed to analyze the particle size. Morphology of the particles was analyzed by light microscopy. The HPH technique produced rutin nanosuspensions having PCS size average of 547–912 nm and zeta potential range about −30 mV in water. Aqueous rutin nanosuspension stabilized by SDS and Tween 80 were stable over 12 months. The nanosuspensions produced via HPH not only could prevent large particle size and particle growth, but also protect the drugs from chemically degradation. The molecules of the surface stabilizer are able to shield the chemical compound. The crystalline structure in a nanoparticulate sized formulation results in improved drug chemical-stability.
    Journal of Pharmaceutical Investigation 10/2013; 43(5). DOI:10.1007/s40005-013-0084-1
  • Valentina Martena · Ranjita Shegokar · Piera Di Martino · Rainer H Müller ·
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    ABSTRACT: Abstract Nicergoline, a poorly soluble active pharmaceutical ingredient, possesses vaso-active properties which causes peripheral and central vasodilatation. In this study, nanocrystals of nicergoline were prepared in an aqueous solution of polysorbate 80 (nanosuspension) by using four different laboratory scale size reduction techniques: high pressure homogenization (HPH), bead milling (BM) and combination techniques (high pressure homogenization followed by bead milling HPH + BM, and bead milling followed by high pressure homogenization BM + HPH). Nanocrystals were investigated regarding to their mean particles size, zeta potential and particle dissolution. A short term physical stability study on nanocrystals stored at three different temperatures (4, 20 and 40 °C) was performed to evaluate the tendency to change in particle size, aggregation and zeta potential. The size reduction technique and the process parameters like milling time, number of homogenization cycles and pressure greatly affected the size of nanocrystals. Among the techniques used, the combination techniques showed superior and consistent particle size reduction compared to the other two methods, HPH + BM and BM + HPH giving nanocrystals of a mean particle size of 260 and 353 nm, respectively. The particle dissolution was increased for any nanocrystals samples, but it was particularly increased by HPH and combination techniques. Independently to the production method, nicergoline nanocrystals showed slight increase in particle size over the time, but remained below 500 nm at 20 °C and refrigeration conditions.
    Drug Development and Industrial Pharmacy 07/2013; 40(9). DOI:10.3109/03639045.2013.810635 · 2.10 Impact Factor

Publication Stats

8k Citations
412.68 Total Impact Points


  • 1992-2015
    • Freie Universität Berlin
      • • Institute of Pharmacy
      • • Division of Pharmaceutical Technology
      Berlín, Berlin, Germany
    • Christian-Albrechts-Universität zu Kiel
      • Department of Pharmaceutics and Biopharmaceutics
      Kiel, Schleswig-Holstein, Germany
  • 2010
    • Universidade Fernando Pessoa
      • Faculty of Health Sciences
      Porto, Distrito do Porto, Portugal
  • 2007
    • Technische Universität Berlin
      Berlín, Berlin, Germany
  • 2003
    • Ludwig-Maximilian-University of Munich
      • Department of Paediatrics
      München, Bavaria, Germany